Gone for good.
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Well I have been invested with Peregrine for over 7 years now and I still need to check the facts before I post them.
I don't consider that as a "misspost" but rather your lack of doing any checking of the facts.
We know that the control arm for the bavi+ doc second-line NSCLC has a MOS of 5.6 months. I don't see a parallel to this BLP25 trial.
You can't use these to really do anything except to find the maximum tolerated dose.
The other phase I trial, which has not been reported on, used radiotherapy with Selectikine.
The EJC paper ends with this statement.
They just published phase I results
A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours
European Journal of Cancer, Vol 49, issue 1, Jan 2013, pp 35-44.
http://www.sciencedirect.com/science/article/pii/S095980491200576X
Conclusions
The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6 mg/kg.
The recommended phase II dose was 0.45–0.6 mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2.
There have been two phase I trials completed. The first one is the subject of the above paper.
EMD 521873 in Advanced Solid Tumors, MTD Finding
http://www.clinicaltrials.gov/ct2/show/NCT01032681?term=EMD+521873&rank=1
EMD 521873 Plus Radiotherapy in Non Small Cell Lung Cancer (NSCLC)
http://www.clinicaltrials.gov/ct2/show/NCT00879866?term=EMD+521873&rank=2
It is not a trial of first-line NSCLC. It was for stage III NSCLC that had previous chemoradiotherapy who
had documented stable disease.
http://www.clinicaltrials.gov/ct2/show/NCT00409188?term=BLP25&rank=11
Why else would the control arm get best supportive care (BSC)? They excluded metastatic disease and
malignant pleural effusion and ECOG PS = 2.
In the previous phase IIB trial for NSCLC patients with stage IIIB and stage IV disease the survival analysis showed
OS increased from 13 to 17.2 months, but it wasn't statistically significant, and again it was for patients who had
stable disease and the control arm got BSC. Upon further analysis most of the OS increase was only in the subgroup
that had stage IIIB local-regional (LR) disease, which was 38% of the patients.
http://link.springer.com/article/10.1007%2Fs00432-011-1003-3
So, in the phase III study they excluded the group that didn't respond well to the treatment in the phase IIB study
and yet it still failed to increase OS.
Where did you get that number for OS?
Yes, the trial did have survival benefit for the squamous cell subgroup with OS increasing from 5.4 to 9 months.
Of course, the bavi trials are all for the non-squamous cell type. There is no reason to think bavi would not work as
well for the squamous cell type. I posted about this trial just to show that yet another chemo combination did not extend
survival in second-line NSCLC. As I noted before, the patients in this trial had a higher percentage with PS = 0,
and less of them had stage IV disease, than in the bavi second-line NSCLC trial.
New trial results for second-line NSCLC with pemetrexed and carboplatin.
Pemetrexed Versus Pemetrexed and Carboplatin As Second-Line Chemotherapy in
Advanced Non–Small-Cell Lung Cancer: Results of the GOIRC 02-2006 Randomized
Phase II Study and Pooled Analysis With the NVALT7 Trial
Journal of Clinical Oncology, Vol 30, Number 36, Dec 20, 2012.
http://jco.ascopubs.org/content/30/36/4501.abstract
There is an ongoing IST trial of pemetrexed + carboplatin + bavi in front-line NSCLC.
http://www.clinicaltrials.gov/ct2/show/NCT01323062?term=bavituximab+OR+Peregrine&recr=Open&rank=3
In the second-line trial above there were two arms. Arm A (standard) received pemetrexed (N=120), and
arm B (experimental) pemetrexed + carboplatin (N=119).
Note that about 82% of the patients had stage IV NSCLC, and about 60% had ECOG PS = 0.
So these patients were healthier than the patients in the bavi + doc second-line NSCLC trial.
We had the same idea that the conference might be a good place to present about the pancreatic trial.
The next conference after that would be the AACR annual meeting.
http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2013.aspx
Abstract submission has ended, except for late breakers.
http://www.aacr.org/home/scientists/meetings--workshops/aacr-annual-meeting-2013/abstracts.aspx#LB
I already pointed out this conference here
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81874861
The deadline for submitting abstracts is well past.
http://www.gicasym.org/2013-call-abstracts
DEADLINE FOR SUBMISSION: September 25, 2012, by 11:59 PM (EDT)
December 6, 2012 Late-Breaking Abstract Deadline (shell abstract must be submitted by Sep 25 deadline)
I have been checking, but so far the abstract titles and authors have not been posted.
This is stuff from the 2008 paper in Nature Medicine
Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases
M Melina Soares, Steven W King & Philip E Thorpe
The freely available paper is here
http://www.nature.com/nm/journal/v14/n12/pdf/nm.1885.pdf
There were also a couple of posters at the Chemical and Biological Defense Science and Technology Conferences
2010:
Targeting of Anionic Phospholipids Exposed on Infected Cells and Virions: Potential broad-Spectrum Antiviral Therapy
Kara Corbin-Lickfett et al.
2011:
Phosphatidylserine Targeting Antibodies as Potential Therapeutic Agents for Argentine Hemorrhagic Fever
Ashley Grant et al.
Abraxane is just another form of paclitaxel. Not a threat to Bavituximab. It might work as a combination
with carboplatin and Bavi in first-line NSCLC. http://en.wikipedia.org/wiki/Abraxane
Here is the report on the phase 3 of Abraxene with carboplatin in first-line NSCLC.
It did not improve OS significantly over regular paclitaxel (solvent based).
http://www.ncbi.nlm.nih.gov/pubmed/22547591
J Clin Oncol. 2012 Jun 10;30(17):2055-62. doi: 10.1200/JCO.2011.39.5848. Epub 2012 Apr 30.
Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin
as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial.
Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, Hon JK, Hirsh V, Bhar P,
Zhang H, Iglesias JL, Renschler MF.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract
PURPOSE:
This phase III trial compared the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) plus
carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus carboplatin in advanced non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS:
In all, 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive
100 mg/m(2) nab-paclitaxel weekly and carboplatin at area under the concentration-time curve
(AUC) 6 once every 3 weeks (nab-PC) or 200 mg/m(2) sb-paclitaxel plus carboplatin AUC 6 once
every 3 weeks (sb-PC). The primary end point was objective overall response rate (ORR).
RESULTS:
On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-PC
(33% v 25%; response rate ratio, 1.313; 95% CI, 1.082 to 1.593; P = .005) and in patients with squamous
histology (41% v 24%; response rate ratio, 1.680; 95% CI, 1.271 to 2.221; P < .001). nab-PC was as effective
as sb-PC in patients with nonsquamous histology (ORR, 26% v 25%; P = .808). There was an approximately
10% improvement in progression-free survival (median, 6.3 v 5.8 months; hazard ratio [HR], 0.902;
95% CI, 0.767 to 1.060; P = .214) and overall survival (OS; median, 12.1 v 11.2 months; HR, 0.922;
95% CI, 0.797 to 1.066; P = .271) in the nab-PC arm versus the sb-PC arm, respectively.
Patients = 70 years old and those enrolled in North America showed a significantly increased OS
with nab-PC versus sb-PC. Significantly less grade = 3 neuropathy, neutropenia, arthralgia, and myalgia
occurred in the nab-PC arm, and less thrombocytopenia and anemia occurred in the sb-PC arm.
CONCLUSION:
The administration of nab-PC as first-line therapy in patients with advanced NSCLC was efficacious
and resulted in a significantly improved ORR versus sb-PC, achieving the primary end point. nab-PC produced
less neuropathy than sb-PC.
You should note that the first link is to the abstract about the preliminary results of the
trial presented at ASCO in 2009, and the second is the paper on the final results of the trial
published in 2011. If you click on the second link you can read the paper. Note that it was
open label, not randomized, and had no control arm. The OS results of 12.2 months is for
the arm which was found to have the maximum tolerated dose (MTD), which had 44 patients.
The OS for all 67 patients at the three dosages was 10.3 months. An important piece of
information is that 50% of the 44 patients had ECOG status = 0, and the other 50% had
ECOG status = 1. So the patient group is somewhat biased towards healthier patients,
which is exactly why a control arm needs to be included.
It would help a little. Last year we paid $23 billion for cancer drugs.
The Cancer “Breakthroughs” that Cost Too Much and Do Too Little
http://www.thedailybeast.com/newsweek/2012/08/26/the-cancer-breakthroughs-that-cost-too-much-and-do-too-little.html
It is all about the atmosphere...
Out of the box thinking. The NIH buys Peregrine for $50 billion. They then run trials on all cancers.
Bavi is provided at cost to all patients. Medicare costs plummet.
Maybe it wouldn't be unreasonable to think that precisely because of all the fuss that was made about the ORR
and PFS differences between the investigators assessment and the central review that Peregrine decided
to wait until they had the final numbers for the control and treatment arm MOS before reporting them.
For the MOS numbers from all the trials we might expect that Peregrine is going to be cautious from now
on and wait until 80% of the patients in each arm have died before reporting the "final" MOS. I could
certainly understand that decision given all that has happened.
The timeline for the development of Bavituximab is very good. I don't think anyone
can say that Peregrine has been slow at this. Tarvacin (later bavituximab) was
announced in this paper published online on May 16, 2005.
A Monoclonal Antibody that Binds Anionic Phospholipids
on Tumor Blood Vessels Enhances the Antitumor Effect of
Docetaxel on Human Breast Tumors in Mice
Xianming Huang, Mary Bennett and Philip E. Thorpe
Cancer Res 2005;65:4408-4416.
http://cancerres.aacrjournals.org/content/65/10/4408.full.pdf+html
The last paragraph:
To me that makes no sense at all. IF Bavi works that well then the BP will make way more money
by getting more approvals for more indications. Why kill it? Any drug that they were
trying to protect will face patent expiration at some point. Where would they be then? The big BPs
are all facing multiple patent expirations now, or very soon, they need new drugs.
If you look at the anti-PS patents they are almost all generated by Thorpe's lab at UTSW Med Center.
This is from the latest one:
Inventors: Thorpe; Philip E. ; (Dallas, TX) ; Soares; M. Melina; (Richardson, TX) ; He; Jin; (Dallas, TX)
Assignee: Board of Regents, The University of Texas System
Peregrine is licensed by the assignee to have exclusive rights to use the patents. My question
is this. If a BP bought Peregrine and then stopped the development of anti-PS, could UT
withdraw the license to use of the patents and make a deal with another company?
UT is only going to make money if they are paid royalties on marketed drugs.
Any patent lawyers out there?
Click on "Avid" at the top of Peregrine's webpage and you will see the PR.
I don't know where this number 3000 comes from. If you search ClinicalTrials.gov for "avastin" and only include
trials that are recruiting you only get 470 trials.
http://www.clinicaltrials.gov/ct2/results?term=avastin&recr=Open&no_unk=Y
A lot of them appear to be smaller IST trials.
I would agree that Bavi needs to be paired with a chemo drug, or with radiation. That has been well documented
in all the preclinical work and is needed to increase the amount of the PS target. I do think that using SBRT (stereotactic
body radiation therapy) with Bavi might turn out to work really well, but that is for future trials to show.
There were many changes made to the prostate trial Clinical Trials webpage now that it
has started recruiting again. Updated Nov 27, 2012.
http://clinicaltrials.gov/archive/NCT01335204/2012_11_27/changes
I was just expressing my observations about the big change in outlook that was presented.
I don't understand the muted response to yesterday's quarterly conference call. I just listened to the question
and answer section a few times. On the second-line NSCLC trial the wording in the PR, and what Steve King says,
could not be in more stark contrast to what I heard at the Annual Shareholders Meeting in October.
From the Peregrine Dec 10 PR:
I think they are the same.
This is what I found about S-1. Mojojojo asked me about these S-1 trials in Japan before.
It turns out that the patient populations had a high percentage with the best performance
status (PS 0), and so that may explain the better response. The FOLFIRINOX regime
is also only recommended for the healthiest of patients.
About S-1
S-1 is a novel oral fluoropyrimidine that combines 3 pharmacological agents:
Tegafur, which is a pro-drug of 5 fluorouracil; gimeracil (5-chloro-2,4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme; and oteracil (potassium oxonate, Oxo) a gastrointestinal side effects corrector.
S-1 is currently marketed in Japan for the treatment of gastric, colorectal, head and neck, non-small cell lung, metastatic breast and pancreas cancers. In the United States, Europe and other countries, the product is in phase III clinical development. Taiho commercializes and develops S-1 in Japan and in a few other countries of Asia. Sanofi-aventis collaborates on the current clinical development and is leading the future clinical development and commercialization of the product in the United States, Europe, and other countries in the world, except certain Asian countries.
I will add another trial. The phase I/II trial in liver cancer. It would be great to get interim survival results.
At the ESMO conference the results of the SEARCH trial were presented. This was a trial of adding Tarceva to sorafenib.
It was a large phase III trial with the goal of increasing survival by 33%, but it failed with only a 12% (1 month) increase in survival.
This is another very hard to treat cancer. If bavi + sorafenib can show even a 50% increase in survival it would be a breakthrough.
Patients with advanced hepatocellular carcinoma show no benefit from adding erlotinib to sorafenib
Category: Vienna 2012 App, Vienna 2012 Congress
Results of the phase III SEARCH trial
The researchers tested whether adjunct erlotinib, a direct and reversible EGFR tyrosine kinase inhibitor, could have synergistic or additive antitumor effects when used with sorafenib in patients with advanced hepatocellular carcinoma. The approach did not improve overall survival or time to progression according to the study report at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.
This phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib enrolled 720 patients with advanced hepatocellular carcinoma aged 18 or more years, ECOG performance status (PS) 0–1 and Child-Pugh class A. Patients were stratified by ECOG PS of 0 or 1, macroscopic vascular invasion and/or presence of extrahepatic spread, smoking status (current, former or never) and by region: the Americas and Europe vs. South Africa and Asia-Pacific.
The patients were randomized 1:1 to receive either continuous treatment with oral sorafenib 400 mg bid plus erlotinib 150 mg daily or sorafenib 400 mg bid plus placebo 150 mg daily and monitored every 6 weeks by CT scans. The primary endpoint of the study, defined as 33% of increase in the overall survival, was not met in this study. Median overall survival in the 362 patients receiving the sorafenib/ erlotinib was 9.5 months compared with 8.5 months in the sorafenib/placebo arm.
Time to progression also did not vary significantly between treatment arms and was 3.2 compared with 4.0 months, with sorafinib/erlotinib and sorafenib/palcebo, respectively. No significant regional differences in overall survival or time to progression were noted. The disease control rates of 43.92% and 52.51% favored the sorafenib/placebo arm. The median treatment duration of 2.8 and 4.0 months was longer with sorafenib/placebo, which reflected the percentage of patients withdrawing after completing one or fewer treatment cycles; the withdrawal rate was 34.0% in the sorafenib/erlotinib arm compared with 23.8% with sorefenib/placebo.
The rates of treatment-emergent and drug-related adverse events were similar between arms; and treatment-emergent and drug-related serious adverse events were also similar (58.0% versus 54.6% and 21.0% versus 22.8% in the sorafenib/erlotinib and sorafenib/placebo arms, respectively). No new or unexpected toxicities were observed between combination treatment and sorafenib or erlotinib alone.
The results reported by Dr. Andrew Zhu and colleagues during Presidential Symposium of the ESMO 2012 Congress, indicate that erlotinib added to sorafenib do not improve overall survival or time to progression over sole sorafenib in patients with advanced hepatocellular carcinoma. Safety profiles were similar between the two treatment groups and consistent with those of each individual agent; however the withdrawal rate was higher in the erlotinib/sorafenib arm, with fewer patients completing one or more cycles.
Discussing the abstract data, Dr Manfred Lutz - a member of the Scientific Committee of ESMO 2012 said that sorafenib remains the standard treatment for patients with advanced hepatocellular carcinoma. He suggested that a subgroup analysis of the SEARCH study is needed for further insight on combo failure. An investigation of combinations with less toxicity is warranted for potential improvements of the treatment outcome in this patient population.
How Peregrine can get an interferon-free Hepatitis C treatment. This is a bit risky, but is it possible?
Remember in August Bristol-Meyers Squibb cancelled all trials involving BMS-986094 (formerly INX-189)
because a patient had died and 8 others were hospitalized with heart problems. This was after BMS had
acquired Inhibitex in January for $2.5 billion.
http://www.nytimes.com/2012/08/24/business/bristol-myers-ends-work-on-hepatitis-c-drug.html
BMS halted all development work on BMS-986094 and will write it off. So it should be very cheap to
buy the rights to BMS-986094. This is an oral drug, as is ribavirin, and both interfere with the replication of the
viral RNA inside the infected host cells. The problem is that the drug is not specific to virus-infected cells
and so causes toxicity in other cells, like heart and kidney cells.
My idea is to covalently bind the drug to a derivative of duramycin and make it into an I.V. drug which
targets virus-infected cells. Duramycin binds very specifically with PE (phosphatidylethanolamine),
which like PS is expressed on the surface of virus-infected host cells. Thorpe has published several papers
showing that PS and PE are also co-located on the tumor vasculature.
The idea is that the duramycin binds to the cell membrane of the virus-infected cell and is then internalized
along with the nucleotide polymerase inhibitor (INX-189). This then stops the replication of the viral RNA inside the cell.
Since the inhibitor is targeted directly to the virus-infected cell the side effect profile should be vastly reduced
and so make it safe. Of course this would have to be all tested with animal models first.
It would be used together with bavituximab and ribavirin to make an interferon-free anti-Hepatitis C cocktail.
Here is an example from
----------------------------------------------------------------------------------------------------------
United States Patent Application 20120164071
Thorpe; Philip E. ; et al. June 28, 2012
Compositions and Methods Comprising Phosphatidylethanolamine-Binding Peptide Derivatives
Abstract
Disclosed are surprising discoveries concerning the role of anionic phospholipids and aminophospholipids in tumor vasculature and in viral entry and spread, and compositions and methods for utilizing these findings in the treatment of cancer and viral infections. Also disclosed are advantageous antibody, immunoconjugate and duramycin-based compositions and combinations that bind and inhibit anionic phospholipids and aminophospholipids, for use in the safe and effective treatment of cancer, viral infections and related diseases.
---------------------------------------------------------------------------------------------------------
Where cidofovir is an anti-viral molecule here attached, via a linker, to duramycin.
http://en.wikipedia.org/wiki/Cidofovir
-----------------------------------------------------------------------------------------------------------
INX-189 is a nucleotide polymerase inhibitor. Here is the structure
http://en.wikipedia.org/wiki/Nucleotide
When you consider that it has been 15 months since the last patient was enrolled in the trial I don't think 20 months
is out of the question. I just hope the control arm is close to that mean of 10 months.
My wishlist for the New Year.
mid-January final MOS data for second-line NSCLC
control arm: 5.6 months
treatment arm: 13 months
mid-February final MOS data for first-line NSCLC
control arm: 10 months
treatment arm: 20 months
mid-March final MOS data for pancreatic cancer
control arm: 6 months
treatment arm: 12 months
Mojojojo,
I think the pancreatic trial could provide such a breakthrough drug. Pancreatic cancer
is the poster child for deadly cancers. Here is a reposting of all 32 pancreatic trials
done and the mean MOS for the gemcitabine arms is 6.6 months, and the treatment
arms only managed a mean MOS of 7.3 months. The bavi + gemcitabine arm could be
at least 10 months now.
I bring this study up again to emphasize that there are many other possibilities for the use of bavituximab.
Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2
immunocytokine that targets exposed phosphatidylserine.
Xianming Huang, Dan Ye, Philip E. Thorpe
Vaccine, 2011 Jun 24;29(29-30):4785-93
You can see the abstract and figures from the paper here:
http://www.sciencedirect.com/science/article/pii/S0264410X11006372
Abstract
Phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane, is immunosuppressive when externalized on the outside of cell membranes. Exposed PS inhibits the maturation and function of dendritic cells (DCs), and induces the production of multiple immunosuppressive mediators. In the present study, we determined whether blocking these effects of PS while simultaneously introducing interleukin-2 (IL-2) could improve the immunogenicity of a whole-cell cancer vaccine. An immunocytokine (2aG4-IL2) was made by genetically linking IL-2 with a PS targeting antibody, 2aG4, that can block the immunosuppressive effects of PS. The 2aG4-IL2/4T1 vaccine was generated by coating the PS exposed on irradiated 4T1 cells with 2aG4-IL2. Tumor growth, spontaneous metastasis, and survival of vaccinated mice challenged with live 4T1 tumor cells were assessed. Eighty percent of mice inoculated with 2aG4-IL2/4T1 vaccine survived free of tumor, as compared with 20% in the 2aG4/4T1 group, 20% in the C44-IL2/4T1 group, and none in the C44/4T1 control group (P=0.001 for 2aG4-IL2/4T1 versus all others groups). The incidence, number of spontaneous lung metastases was significantly lower in the 2aG4-IL2/4T1 vaccinated group than in the other groups. Splenocytes from 2aG4-IL2/4T1 vaccinated mice had significantly higher 4T1 specific cytotoxicity and ability to secrete interferon-gamma (IFN?) than did splenocytes from mice in the other groups. These results demonstrate that a potent whole-cell vaccine can be created by coating irradiated tumor cells with 2aG4-IL2. Such vaccine could potentially be an effective treatment modality for patients with residual disease or at "high-risk" for recurrence.
From today's NY Times online
In Girl’s Last Hope, Altered Immune Cells Beat Leukemia
http://www.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-using-altered-t-cells.html?pagewanted=1&ref=global-home
and from last year
An Immune System Trained to Kill Cancer
http://www.nytimes.com/2011/09/13/health/13gene.html?pagewanted=all&_r=0
while these two articles don't have anything to do with bavituximab directly, they do show the power of the immune system to defeat cancer.
I don't think a diagnosis is arrived at by just the PSA test or mammogram, rather a biopsy is done.
Those can also be false positives, but are much more reliable. The chart just gives estimates.